Efforts to develop more effective treatment approaches for alcohol dependence will benefit from two lines of research: 1) a more precise characterization of the neurobiological mechanisms that underlie responses to alcohol cues and relapse; and 2) the identification of biomarkers (e.g., genetic variations) that reflect the functional significance of these mechanisms on an individual level, such that they might be used to match individuals with the treatment most likely to be effective for them. Consistent with these two overarching objectives, our focus over the last five years of support has been to integrate neuroimaging and genetic approaches to more precisely characterize the neurobiological mechanisms that putatively underlie reactivity to alcohol cues and to identify biomarkers associated with those mechanisms. The focus of data analyses to date has been the characterization of fMRI BOLD response to the presentation of alcohol cues (i.e., the taste of alcohol) and genetic variations that predict that response in a sample of 270 individuals with an alcohol use disorder. The results (see preliminary studies section) provide strong initial support for 100 single nucleotide polymorphisms (SNPs) that are associated with cue-elicited BOLD response in the striatum and prefrontal cortex. The overarching aim of this application for continuation of funding is to follow-up these analyses with an a priori hypothesis driven study designed to replicate individual SNP results. The research will also examine years of heavy alcohol abuse as an environmental variable that may interact with genetic variation to exacerbate changes in neuronal function in a sample of 320 individuals with alcohol use disorders.